A putative placebo analysis of the effects of LCZ696 on clinical outcomes in heart failure.
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McMurray John, Packer Milton, Desai Akshay, Gong Jianjian, Greenlaw Nicola, Lefkowitz Martin, Rizkala Adel, Shi Victor, Rouleau Jean, Solomon Scott, Swedberg Karl, Zile Michael R, Andersen Karl, Arango Juan Luis, Arnold Malcolm, Bĕlohlávek Jan, Böhm Michael, Boytsov Sergey, Burgess Lesley, Cabrera Walter, Chen Chen-Huan, Erglis Andrejs, Fu Michael, Gomez Efrain, Gonzalez Angel, Hagege Albert-Alain, Katova Tzvetana, Kiatchoosakun Songsak, Kim Kee-Sik, Bayram Edmundo, Martinez Felipe, Merkely Bela, Mendoza Iván, Mosterd Arend, Negrusz-Kawecka Marta, Peuhkurinen Keijo, Ramires Felix, Refsgaard Jens, Senni Michele, Sibulo Antonio S, Silva-Cardoso José, Squire Iain, Starling Randall C, Vinereanu Dragos, Teerlink John R, Wong Raymond, PARADIGM-HF Committees and Investigators
Аннотация
METHODS AND RESULTS: We used the treatment-arm of the Studies Of Left Ventricular Dysfunction (SOLVD-T) as the reference trial for comparison of an ACE inhibitor to placebo and the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity-Alternative trial (CHARM-Alternative) as the reference trial for comparison of an ARB to placebo. The hazard ratio of LCZ696 vs. a putative placebo was estimated through the product of the hazard ratio of LCZ696 vs. enalapril (active-control) and that of the historical active-control (enalapril or candesartan) vs. placebo. For the primary composite outcome of cardiovascular death or heart failure hospitalization in PARADIGM-HF, the relative risk reduction with LCZ696 vs. a putative placebo from SOLVD-T was 43% (95%CI 34–50%; P < 0.0001) with similarly large effects on cardiovascular death (34%, 21–44%; P < 0.0001) and heart failure hospitalization (49%, 39–58%; P < 0.0001). For all-cause mortality, the reduction compared with a putative placebo was 28% (95%CI 15–39%; P < 0.0001). Putative placebo analyses based on CHARM-Alternative gave relative risk reductions of 39% (95%CI 27–48%; P < 0.0001) for the composite outcome of cardiovascular death or heart failure hospitalization, 32% (95%CI 16–45%; P < 0.0001) for cardiovascular death, 46% (33–56%; P < 0.0001) for heart failure hospitalization, and 26% (95%CI 11–39%; P < 0.0001) for all-cause mortality.
CONCLUSION: These indirect comparisons of LCZ696 with a putative placebo show that the strategy of combined angiotensin receptor blockade and neprilysin inhibition led to striking reductions in cardiovascular and all-cause mortality, as well as heart failure hospitalization. These benefits were obtained even though LCZ696 was added to comprehensive background beta-blocker and mineralocorticoid receptor antagonist therapy.